We have assembled a multidisciplinary team which is highly accomplished in clinical research, genomics, and bioinformatics/biostatistics, with the goal to identify prognostic biomarkers to better predict and understand progression of chronic lymphocytic leukemia (CLL). The course of CLL is variable and its pathogenesis is poorly understood: while some patients have long-term indolent disease prior to progression, others progress rapidly requiring therapy within a relatively short time after diagnosis. Although existing biomarkers and clinical factors can stratify patients into high and low risk groups, there remains a need for longitudinal biomarkers which can signal development of progressive disease after a variable indolent period. We have a large number of clinically well-annotated CLL tissue samples with long term follow-up on outcome, available from the UCSD site of the CLL Clinical Research Consortium (CRC). Samples include viably-frozen leukemia cells, leukemia-cell DNA, RNA, and germline DNA. We propose a retrospective matched case-control study comparing an early-progressing group of CLL patients (n=12) with a later-progressing (n=12) and a long-term indolent group (n=12). The later-progressing and long-term indolent groups are individually matched on gender and time to progression or time to last follow-up, respectively. All three groups have two blood draws within the first two years;the later-progressing and long-term progression-free patients also have a matched third blood draw between 3 and 8 years after diagnosis. We will use second-generation sequencing to generate transcriptome data for these 96 CLL tumor samples (12 early-progressing, sampled at 2 time points;24 later-progressing and long-term indolent, sampled at 3 time points). We will quantify mRNA transcript levels for genes and for alternative splice isoforms, and identify recurrent mutations. We will use these data to identify candidate biomarkers at baseline, and then identify candidate longitudinal biomarkers by finding differences between early-progressing and the other two groups in the change score during the first two years. We will validate these candidate longitudinal biomarkers by assessing them for significant differences between later progressing and long-term indolent groups after three years. Finally, we will integrate putative longitudinal biomarkers with existing known prognostic factors in the clinical database. If successful, our candidate biomarkers will be well poised to carry forward for further validation in the full CRC biorepository, and to propose for prospective clinical studies. PUBLIC HEALTH RELEVANCE: Project Narrative Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia in the United States. Here we seek to improve the health care of CLL patients by developing biomarkers to better predict and understand disease progression.